Novel hydrate forms of alendronate sodium, processes for manufacture thereof, and pharmaceutical compositions thereof

ABSTRACT

New hydrate forms of alendronate sodium, having water content of between about one and about twelve percent, and processes for their manufacture, are disclosed. New crystalline forms of alendronate sodium B, D, E, F, G and H, and processes for manufacturing them, are also disclosed. These new forms of alendronate sodium are suitable for incorporation into pharmaceutical compositions for combating bone resorption in bone diseases.

FIELD OF THE INVENTION

[0001] This invention relates to new hydrate and crystalline forms ofalendronate sodium, processes for the manufacture thereof, andpharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

[0002] Alendronate sodium, the sodium salt of alendronic acid, alsoknown as 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium,has the formula I:

[0003] It is an agent for combating bone resorption in bone diseasesincluding osteoporosis and Paget's disease.

[0004] Various methods for preparing alendronic acid are known in theart and have been disclosed in M. I. Kabachnik et al., Synthesis andAcid-Base and Complexing Properties of Amino-Substitutedα-Hydroxyalkylidene-diphosphonic Acids, Izv. Akad. Nauk USSR, Ser. Khim,2,433 (1978) and in U.S. Pat. Nos. 4,407,761, 4,621,077, 4,705,651,5,039,819 and 5,159,108.

[0005] U.S. Pat. No. 4,922,007 describes the preparation of a trihydrateof alendronate sodium by reaction of 4-aminobutyric acid withphosphorous acid and phosphorous trichloride in the presence ofmethanesulfonic acid followed by the addition of sodium hydroxide.

[0006] The present invention provides new hydrate forms of alendronatesodium, having water content of 1.3 to 11.7 percent, and processes fortheir manufacture. Moreover, the present invention provides newcrystalline forms of alendronate sodium, designated forms B, D, E, F, Gand H, and processes for the manufacture thereof.

OBJECTS AND SUMMARY OF THE INVENTION

[0007] The present invention provides novel hydrate forms of alendronatesodium having water content of between 1.3 and 11.7 percent water.Typically, but without limitation, the present invention relates to thefollowing novel hydrate forms forms of alendronate monosodium: 1/4hydrate, 1/3 hydrate, hemihydrate, 2/3 hydrate, 3/4 hydrate,monohydrate, 5/4 hydrate. 4/3 hydrate, 3/2 hydrate, 5/3 hydrate, 7/4hydrate and dehydrate.

[0008] The-present invention provides a new crystalline Form B ofalendronate sodium, having a powder x-ray diffractogram substantially asdepicted in FIG. 1a, with characteristic peaks at 12.2±0.2, 13.3±0.2,14.8±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 19.4±0.2, 21.3±0.2,22.6±0.2, 23.2±0.2, 24.0±0.2, 25.2±0.2, 25.8±0.2, 27.4±0.2, 29.4±0.2,and 36.0±0.2 degrees 2 theta. Alendronate sodium Form B has significantIR bands as depicted in FIG. 1b at 654 cm⁻¹, 955 cm⁻¹, 1074 cm-1, 1261cm⁻¹, 1309 cm⁻¹, and 1614 cm⁻¹. The TGA curve, FIG. 1c, shows a cleartwo-step loss on drying of 7.2%, which implies that the crystal form Bcontains a stoichiometric quantity of water close to that of themonohydrate (expected loss on drying value: 6.2%).

[0009] Another embodiment of the invention is a new crystalline Form Dof alendronate sodium, having a powder X-ray diffractogram substantiallyas depicted in FIG. 4a, with characteristic peaks at 13.1±0.2, 15.2±0.2,16.3±0.2, 18.4±0.2, 20.8±0.2, 22.3±0.2, 22.5±0.2, 23.4±0.2, 23.7±0.2,31.4±0.2, and 35.7±0.2 degrees 2 theta. Form D as depicted in FIG. 4 bhas significant IR bands at 662 cm⁻¹, 919 cm⁻¹, 934 cm⁻¹, 954 cm⁻¹, 1054cm⁻¹, 1072 cm⁻¹ 1297 cm⁻¹ and 1318 cm⁻¹. The TGA curve, as depicted inFIG. 4c, shows a gradual loss on drying of 4.1% up to 180° C.

[0010] An additional embodiment is a new crystalline Form E ofalendronate sodium, having a powder X-ray diffractogram substantially asdepicted in FIG. 5a, with characteristic peaks at 7.0±0.2, 9.3±0.2,11.8±0.2, 13.3±0.2, 14.0±0.2, 15.3±0.2, 16.2±0.2, 19.4±0.2 degrees 2theta. Form E has significant IR bands as depicted in FIG. 5b at 660cm⁻¹, 897 cm⁻¹, 924 cm⁻¹, 953 cm⁻¹, 970 cm⁻¹, 1017 cm⁻¹, 1040 cm⁻¹, 1093cm⁻¹ 149 cm⁻¹, 1177 cm⁻¹, 1252 cm⁻¹ 1293 cm⁻¹ 1337 cm⁻¹, 1535 cm⁻¹, 1606cm⁻¹, and 1639 cm⁻¹. The TGA curve, as depicted in FIG. 5c, shows agradual loss on drying of 4.1% up to 150° C.

[0011] A still further embodiment of the invention is a new crystallineForm F of alendronate sodium, having a powder X-ray diffractograrnsubstantially as depicted in FIG. 6a, with characteristic peaks at9.3±0.2, 11.7±0.2, 13.0±0.2, 13.4±0.2, 14.2±0.2, 15.3±0.2, 16.2±0.2,17.4±0.2, 19.1±0.2, 19.4±0.2 and 25.5±0.2 degrees 2 theta. Form F hassignificant IR bands as depicted in FIG. 6b at 660 cm⁻¹, 893 cm⁻¹, 930cm⁻¹, 9953 cm⁻¹, 970 cm⁻¹, 982 cm⁻¹, 1010 cm⁻¹, 1033 cm⁻¹ 1052 cm⁻¹,1060 cm⁻¹, 1069 cm⁻¹, 1109 cm⁻¹ and 1169 cm⁻¹, 1251 cm⁻¹, 1338 cm⁻¹,1498 cm⁻¹, 1544 cm⁻¹, 1603 cm⁻¹, 1637 cm⁻¹, 1664 cm⁻¹. The TGA FIG. 5ccurve shows a gradual loss on drying of 4.1% up to 150° C.

[0012] A further embodiment is a new crystalline Form G of alendronatesodium, having a powder X-ray diffractogram substantially as depicted inFIG. 7a, with characteristic peaks at 9.5±0.2, 10.1±0.2, 12.7±0.2,16.2±0.2, 17.3±0.2, 17.6±0.2, 19.1±0.2, 20.4±0.2, 20.9±0.2, 22.1±0.2,24.8±0.2, 25.5±0.2, 28.0±0.2, 29.0±0.2, 29.6±0.2, 30.4±0.2, 32.4±0.2,and 32.8±0.2 degrees 2 theta. Form G has significant IR bands asdepicted in FIG. 7b at 665 cm⁻¹, 751 cm⁻¹, 856 cm⁻¹, 895 cm⁻¹, 913 cm⁻¹,939 cm⁻¹, 1011 cm⁻¹, 1021 cm⁻¹, 1050 cm⁻¹, 1091 cm⁻¹, 1155 cm⁻¹, 1273cm⁻¹, 1305 cm⁻¹, 1337 cm⁻¹, 1510 cm⁻¹, and 1639 cm⁻¹. The TGA curve,FIG. 7c, shows a loss on drying of 6.5% which indicates that the crystalform G contains a stoichiometric quantity of water corresponding to thatof the monohydrate (expected loss on drying value: 6.2%). This TGA stepis sharp and occurs at 195° C. The relatively high temperature ofdehydration implies that the water is bound tightly to the alendronatemolecule. The dehydration step is immediately followed by another stepdue to decomposition. Due to the decomposition process that occursadjacent to the dehydration, the conventional loss of drying method isnot feasible, and for loss on drying determination the TGA is used.

[0013] Yet another embodiment is a new crystalline Form H of alendronatesodium, having a powder X-ray diffractogram substantially as depicted inFIG. 8a, with characteristic peaks at 9.2±0.2, 13.0±0.2, 14.2±0.2,15.0±0.2, 17.1±0.2, 20.7±0.2, 22.0±0.2, 22.4±0.2, degrees two theta.Form H has significant IR bands, as depicted in FIG. 8b, of 664 cm⁻¹,688 cm⁻¹, 722 cm⁻¹, 751 cm⁻¹, 863 cm⁻¹, 893 cm⁻¹, 918 cm⁻¹, 936 cm⁻¹,984 cm⁻¹, 1010 cm⁻¹, 1036 cm⁻¹, 1052 cm⁻¹, 1092 cm⁻¹, 1157 cm⁻¹, 1273cm⁻¹, 1303 cm⁻¹ and 1338 cm⁻¹, 1499 cm⁻¹, 1598 cm⁻¹, 1636 cm⁻¹, and 1664cm⁻¹. The TGA curve FIG. 8c shows a sharp loss on drying of 3.7% at 170°C.

[0014] All of sodium alendronate crystalline forms B, D, E, F, G and Hcontain water in the amount of 2.2 to 9.0% by weight.

[0015] The invention further provides a new hydrate form of alendronatesodium having a water content of 1.3% to 3.1%.

[0016] A further embodiment is a new hydrate form of alendronate sodiumhaving a water content of 2.5% to 3.5%.

[0017] A further embodiment is a new hydrate form of alendronate sodiumhaving a water content of 2.8% to 3.9%.

[0018] An additional embodiment is a new hydrate form of alendronatesodium having a water content of 3.2% to 5.8%.

[0019] Another embodiment is a new hydrate form of alendronate sodiumhaving a water content of 5.1% to 7.0%.

[0020] A still further embodiment is a new hydrate form of alendronatesodium having a water content of 6.4% to 9.0%.

[0021] The invention also provides a new crystalline Form B ofalendronate sodium, having a water content of 6.4% to 9.0%.

[0022] The invention further provides a new crystalline Form D ofalendronate sodium, having a water content of 3.2% to 5.8%.

[0023] The invention further provides a new crystalline Form F ofalendronate sodium, having a water content of 1.3% to 3.1%.

[0024] The invention further provides a new crystalline Form G ofalendronate sodium, having a water content of 5.1% to 7.0%.

[0025] The invention further provides a new crystalline Form E ofalendronate sodium, having a water content of 2.8% to 3.9%.

[0026] The invention further provides a new crystalline Form H ofalendronate sodium, having a water content of 2.5% to 3.5%.

[0027] The invention provides a new monohydrate and a new dehydrate ofalendronate sodium, having an X-ray diffractogram substantially asdepicted in FIG. 2a and 3 a, accordingly, with characteristic peaks at9.3±0.2, 12.4±0.2, 13.5±0.2, 17.1±0.2, 18.5±0.2, 19.7±0.2, 20.3±0.2,21.0±0.2, 21.8±0.2, 23.4±0.2, 24.3±0.2. 24.9±0.2, 26.3±0.2. 30.0±0.2,and 34.4±0.2 degrees 2 theta. Form C as depicted in FIGS. 2b and 3 b hassignificant IR bands at 660 cm⁻¹, 745 cm⁻¹, 865 cm⁻¹, 913 cm⁻¹, 952cm⁻¹, 966 cm⁻¹, 1017 cm⁻¹, 1046 cm⁻¹, 1128 cm⁻¹, 1174 cm⁻¹, 1235 cm⁻¹,1340 cm⁻¹, 1402 cm⁻¹, 1544 cm⁻¹, 1606 cm⁻¹, and 1644 cm⁻¹. The TGA curveof the monohydrate Form C (FIG. 2c shows a loss on drying of 5.6% whichimplies that the crystal Form C contains a stoichiometric quantity ofwater close to that of the monohydrate (expected loss on drying value:6.2%). The TGA curve of the dehydrate Form C (FIG. 3c) shows a sharp Closs on drying of 12.0% which implies that the crystal Form C contains astoichiometric quantity of water corresponding to dehydrate (expectedloss on drying value: 11.7%).

[0028] The present invention also relates to the method of preparing thecompound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodiumsalt having water content of 1.3% to 11.7% by reacting alendronic acidwith one equivalent of sodium base in an aqueous organic solventselected from the group consisting of. acetone, DMSO, DMF, acetonitrile,alcohols, polyalcohols and/or their ethers, pyridine, sulfolane,N-methyl pyrrolidinone and dioxane.

[0029] The invention further provides a method for making Form D ofalendronate sodium, comprising treating alendronic acid anhydrous in alower alkanol with 1 equivalent of sodium base and 0 to 4 equivalents ofwater, followed by isolating the crystalline alendronate sodium Form D.

[0030] The invention further provides a method for making Form E ofalendronate sodium, comprising treating alendronic acid, which is inanhydrous or monohydrate form, in a lower alkanol with I equivalent ofsodium base and 9 to 15 equivalents of water, followed by isolating thecrystalline alendronate sodium Form E.

[0031] The invention further provides a method for making Form F ofalendronate sodium, comprising treating alendronic acid, in a loweralkanol with 1 equivalent of sodium base and 5 to 8 equivalents of waterfor anhydrous form and 3 to 20 equivalents of water for monohydrateform, followed by isolating the crystalline alendronate sodium Form F.

[0032] The invention further provides a method for making alendronatesodium monohydrate, comprising treating alendronic acid, in a loweralkanol with 1 equivalent of sodium base and water under the conditionsdescribed hereinafter, followed by isolating the alendronate sodiummonohydrate. The invention further provides a method for making Form Gof alendronate sodium, comprising treating alendronic acid, in a loweralkanol with 1 equivalent of sodium base and water under the conditionsdescribed hereinafter, followed by isolating the crystalline alendronatesodium Form C.

[0033] Typical but not limiting conditions for preparing alendronatesodium Form G are as described in the following table: Range of StartingAlendronic Preferred Range of Water Acid Hydrate Form Solvent WaterEquivalent Equivalent Monohydrate Methanol 20-200 40-175 MonohydrateEthanol 15-100 20-80  Monohydrate Isopropanol 5-40 10-20  AnhydrousMethanol 50-125 80-100 Anhydrous Ethanol 15-40  25-35 

[0034] The invention further provides a method for making Form G ofalendronate sodium comprising treating any one or more of the crystalforms of alendronate sodium selected from the group which consists ofForm B, Form C, Form D, Form E, Form F and Form H, in a lower alkanol,preferably ethanol, with 20-40 equilvalents of water under theconditions described hereinafter followed by isolating the crystallinealendronate sodium Form G.

[0035] The invention further provides a method for making Form G ofalendronate sodium comprising treating alendronate monosodium trihydratein a lower alkanol, preferably ethanol, with 25-35 equivalents of waterunder the condition described hereinafter, followed by isolating thecrystalline alendronate sodium Form G.

[0036] The invention further provides a method for making Form G ofalendronate sodium comprising treating any one or more forms ofalendronate sodium salts preferably selected from the group consistingof monosodium, disodium, trisodium and tetrasodium salts, in a loweralkanol preferably ethanol with 20-40 equivalents of water under theconditions described hereinafter, followed by isolating the crystallinealendronate sodium Form G. In the event that the starting sodium salt ishigher than monosodium (e.g. disodium, trisodium or tetrasodium) it isnecessary to add an acid, preferably alendronic acid, in order tomaintain the pH at about 4.4.

[0037] The invention further provides a method for making Form H ofalendronate sodium, comprising treating alendronic acid, which is theanhydrous or monohydrate form, in a lower alkanol with one equivalent ofsodium base and 25 to 35 equivalents of water, under the conditionsdescribed hereinafter, followed by isolating the crystalline alendronatesodium Form H.

[0038] The invention further provides a method for making Form B ofalendronate sodium, comprising treating alendronic acid monohydrate in alower alkanol with one equivalent of sodium base and 0 to 4 equivalentsof water, followed by obtaining the crystalline alendronate sodium FormB.

[0039] The invention further provides a method for making alendronatesodium dehydrate comprising treating crystalline alendronate sodiumtrihydrate with an effective amount of drying agent followed byisolating the crystalline alendronate sodium dehydrate.

[0040] The invention further provides a method for making alendronatesodium monohydrate comprising treating crystalline alendronate sodiumtrihydrate with a sufficient amount of drying agent followed byisolating the crystalline alendronate sodium monohydrate.

[0041] The invention further provides a method for making alendronatesodium monohydrate comprising treating crystalline alendronate sodiumdehydrate with a sufficient amount of drying agent followed by isolatingthe crystalline alendronate sodium monohydrate.

[0042] The invention further relates to a pharmaceutical compositionwhich comprises alendronate sodium, having water content of 1.3 to 11.7percent in a therapeutically effective amount, and a pharmaceuticallyacceptable carrier.

[0043] The invention further relates to a pharmaceutical compositionwhich comprises alendronate sodium in Form B D, E, F, G and/or H in atherapeutically effective amount, and a pharmaceutically acceptablecarrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0044]FIGS. 1a, 1 b, and 1 c show, respectively, the powder X-raydiffraction spectrum, the thermograviometric (TGA) curve and theinfrared spectrum of alendronate sodium Form B.

[0045]FIGS. 2a, 2 b, and 2 c show, respectively, the powder X-raydiffraction spectrum, the thermograviometric (TGA) curve and theinfrared spectrum of alendronate sodium monohydrate Form C.

[0046]FIGS. 3a, 3 b, and 3 c show, respectively, the powder X-raydiffraction spectrum, the thermograviometric (TGA) curve and theinfrared spectrum of alendronate sodium dehydrate Form C.

[0047]FIGS. 4a, 4 b, and 4 c show, respectively, the powder X-raydiffraction spectrum, the thermograviometric (TGA) curve and theinfrared spectrum of alendronate sodium Form D.

[0048]FIGS. 5a, 5 b, and 5 c show, respectively, the powder X-raydiffraction spectrum, the (thermograviometric (TGA) curve) and theinfrared spectrum of alendronate sodium Form E.

[0049]FIGS. 6a, 6 b, and 6 c show, respectively, the powder X-raydiffraction spectrum, the thermograviometric (TGA) curve and theinfrared spectrum of alendronate sodium Form F.

[0050]FIGS. 7a, 7 b, and 7 c show, respectively, the powder X-raydiffraction spectrum, the then-nograviometric (TGA) curve and theinfrared spectrum of alendronate sodium Form G.

[0051]FIGS. 8a, 8 b and 8 c show respectively the powder X-raydiffraction spectrum, the thermograviometric (TGA) curve and theinfrared spectrum of alendronate sodium of Form H.

DETAILED DESCRIPTION OF THE INVENTION

[0052] The invention discloses new hydrate forms of alendronate sodiumhaving water contents of 1.3 percent to 11.7 percent.

[0053] The present invention also discloses new crystalline forms ofalendronate sodium which have been designated Forms B, D, E, F, G and H.

[0054] The term “water content” refers to the content of water basedupon the Loss on Drying method as described in Pharmacopeial Forum, Vol.24, No. 1, page 5438 (Jan-Feb 1998). The calculation of water content isbased upon the percent of weight that is lost by drying. For Forms G andH the term “water content” refers to the content of water based upon aTGA measurement and a step analysis in the temperature range of about25° C.-215° C. for Form G, and 25° C.-200° C. for Form H.

[0055] The term “lower alkanol” refers to alkanols having 1 to 4 carbonatoms. Preferred lower alkanols include ethanol, methanol andisopropanol.

[0056] The term “equivalents of water” means molar equivalents of water.

[0057] The term “equivalents of sodium base” means molar equivalents ofsodium base.

[0058] Those skilled in the art will appreciate that the termmonohydrate” when used in reference to alendronic acid describes acrystalline material having a water content of 6.7%. Those skilled inthe art will also understand that the term “anhydrous” when used inreference to alendronic acid describes alendronic acid that issubstantially free of water.

[0059] One of skill in the art will appreciate that the term“monohydrate” when used in reference to the monosodium salt ofalendronic acid describes a crystalline material having a water contentof approximately 6.2%.

[0060] One skilled in the art will also appreciate that the term“dehydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 11.7%.

[0061] One skilled in the art will also appreciate that the term “1/4hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 1.6%.

[0062] One skilled in the art will also appreciate that the term “1/3hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 2.1%.

[0063] One skilled in the art will also appreciate that the term“hemihydrate” when used in reverence to the monosodium salt ofalendronic acid describes a crystalline material having a water contentof approximately 3.2%.

[0064] One skilled in the art will also appreciate that the term “2/3hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 4.2%.

[0065] One skilled in the art will also appreciate that the term “3/4hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 4.7%.

[0066] One skilled in the art will also appreciate that the term “5/4hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 7.6%.

[0067] One skilled in the art will also appreciate that the term “4/3hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 8.1%.

[0068] One skilled in the art will also appreciate that the term “3/2hydrate” when used in reference to the monosodium salt of alendronicacid describes a crystalline material having a water content ofapproximately 9.1%.

[0069] Finally, those skilled in the art will appreciate that the term“trihydrate” when used in reference to the monosodium salt of alendronicacid refers to a crystalline material having a water content ofapproximately 16.6%.

[0070] The term “sodium base” refers to sodium hydroxide and the sodiumalkoxide of a lower alkanol.

[0071] Alendronic acid can be prepared by methods that are well known inthe art. MI Kabachnik et al., Izv. Akad. Nauk USSR, Ser. Khim, 2, 433(1978) discloses a reaction for making alendronic acid;

[0072] Alendronic acid can also be prepared by the process disclosed inU.S. Pat. No. 4,621,077. It will be appreciated that when alendronicacid is recrystallized from water, as in the above process, themonohydrate is formed.

[0073] Alendronate sodium trihydrate can be prepared by the processdisclosed in U.S. Pat. No. 4,922,007.

[0074] The contents of all references cited are incorporated byreference.

[0075] Alendronic acid monohydrate can be converted to alendronic acidanhydrous by heating in a vacuum oven at 110-220° C. at a vacuum of lessthan 5 mm Hg for 24 hours.

[0076] In accordance with the process aspect of the present invention,alendronic acid anhydrous as prepared by any of the known methods isadded to a lower alkanol, preferably ethanol, together with a sodiumbase, preferably sodium hydroxide, and an amount of water that dependsupon the desired crystal form of alendronate sodium. The molar ratio ofsodium base to alendronic acid is 1:1. Those skilled in the art willappreciate that a higher ratio of NaOH would yield the undesirabledisodium and trisodium salts. The reaction mixture is boiled underreflux while being stirred vigorously for approximately 15 hours, untilthe pH of the liquid phase remains constant (approx. pH 7). Crystallinealendronate sodium is then isolated, preferably by filtration aftercooling to ambient temperature, washing with absolute ethanol,optionally washing with absolute ethyl ether and drying overnight in avacuum oven at ambient temperature and at a pressure of 10 mm to 15 mmof mercury. For the purposes of this specification, ambient temperatureis from about 20°0 C. to about 25° C.

[0077] In accordance with the aspects of this invention whereinalendronic acid monohydrate is converted to,alendronate sodium,alendronic acid monohydrate as prepared by any of the known methods isadded to an alkanol, preferably ethanol, together with a sodium base,preferably sodium hydroxide, and a desired amount of water. The amountof water depends upon the crystal form that is desired. The molar ratioof sodium base to alendronic acid is 1:1. The reaction mixture is boiledunder reflux while stirring vigorously for approximately 15 hours, untilthe pH of the liquid phase remains constant (approx. pH 7). Crystallinealendronate sodium is then isolated, preferably by filtration aftercooling to ambient temperature followed by washing with absoluteethanol, washing with absolute ether and drying overnight in a vacuumoven at ambient temperature and at a pressure of 10 mm to 15 mm ofmercury.

[0078] In accordance with the aspects of this invention whereinalendronate sodium trihydrate (Form C) is converted to alendronatesodium dehydrate (Form C), alendronate sodium trihydrate as prepared bymethods known in the art is added to an alkanol which is substantiallyfree of water, preferably absolute ethanol. This mixture is treated witha drying agent, preferably by refluxing the mixture in a refluxcondenser wherein the condensate formed passes through 3 Å molecularsieves. The weight:weight ratio of molecular sieves to alendronatesodium trihydrate is preferably about 2:1 and most preferably 12:5.Refluxing of the mixture is preferably done for 24 hours with stirring.Alendronate sodium dehydrate is then isolated, preferably by filtrationafter cooling to ambient temperature, washing with absolute ether anddrying overnight in a vacuum oven at ambient temperature and at apressure of 10 mm to 15 mm of mercury.

[0079] In accordance with the aspects of this invention whereinalendronate sodium trihydrate (Form C) is converted to alendronatesodium monohydrate (Form C), alendronate sodium trihydrate as preparedby any of the methods known in the art is added to an alkanol which issubstantially free of water, preferably absolute ethanol. This mixtureis treated with a drying agent, preferably by refluxing the mixture in areflux condenser wherein the condensate formed passed through 3 Åmolecular sieves. If and when a first portion of molecular sieves isexhausted, a second portion of fresh molecular sieves is used. Theweight:weight ratio of molecular sieves to alendronate sodium trihydrateis preferably about 2:1 and most preferably 12:5. Refluxing of themixture is preferably done for 24 hours with stirring. The mixture isallowed to cool to ambient temperature before recharging with anequivalent amount of molecular sieves. Alendronate sodium monohydrate isthen isolated, preferably by cooling to ambient temperature, filtration,washing with absolute ether and drying overnight in a vacuum oven atambient temperature and a pressure of 10 mm and 15 mm of mercury.

[0080] In accordance with the present invention, the new crystallineforms of alendronate sodium and the new hydrate forms of alendronatesodium may be prepared as pharmaceutical compositions which areparticularly useful for the treatment of bone resorption in bonediseases including osteoporosis and Paget's disease. Such compositionsmay comprise one of the new crystalline and hydrate forms of alendronatesodium with pharmaceutically acceptable carriers and/or excipients.

[0081] For example, these compositions may be prepared as medicaments tobe administered orally, parenterally, rectally, transdermally, bucally,or nasally. Suitable forms for oral administration include tablets,compressed or coated pills, dragees, sachets, hard or gelatin capsules,sub-lingual tablets, syrups and suspensions; for parenteraladministration the invention provides ampoules or vials that include anaqueous or nonaqueous solution or emulsion; for rectal administrationthere are provided suppositories with hydrophilic or hydrophobicvehicles; and for topical application as ointments or aerosolformulations known in the art; transdermal delivery there are providedsuitable delivery systems as known in the art; and for nasal deliverythere are provided suitable aerosol delivery systems known in the art.

[0082] The powder X-ray diffraction patterns were obtained by methodsknown in the art using a Philips X-Ray powder diffractometer, Goniometermodel 1050/70 at a scanning speed of 2° per minute.

[0083] The thermogravimetric curves were obtained by methods known inthe art using a Mettler TGA TG50. The weight of the samples was about 10mg. The temperature range was from 25° C. to at least 200° C., at therace of 10° C./min. Samples were purged with mitrogen gas at a flow rateof 40 ml/min. Standard 150 ml aluminum crucibles were used.

[0084] The infrared spectra were obtained by methods known in the artusing a Perkin Elmer FT-IR Paragon 1000 spectrometer. Samples wereanalyzed in Nujol mulls. Spectra were obtained at 4 cm⁻¹ resolution and16 scans each.

[0085] The atomic absorption analysis was obtained by methods known inthe art using a Perkin Elmer 5000 Flame Atomic Absorption instrument.Sodium content was determined against standard solutions obtained fromMerck and Aldrich.

EXAMPLES

[0086] This invention will be better understood from the experimentaldetails which follow. However, one skilled in the art will readilyappreciate that the specific methods and results discussed are merelyillustrative of the invention as described more fully in the claims thatfollow thereafter.

Example 1 Preparation of Alendronic Acid Monohydrate

[0087] Alendronic acid was crystallized from water to make alendronicacid monohydrate. The resulting alendronic acid monohydrate was dried at50° C. at 10 mm Hg pressure for 15 hours to give dry alendronic acidmonohydrate containing 6.9% water.

Example 2 Preparation of Anhydrous Alendronic Acid

[0088] The alendronic acid monohydrate from Example 1 was further driedat 110-120° C. in 1 mm Hg for 4 hours to give anhydrous alendronic acid.The water content was 0.3% by weight.

Example 3 Preparation of Alendronate Sodium from Anhydrous AlendronicAcid

[0089] A 250 ml flask was fitted with a mechanical stirrer, athermometer, and a reflux condenser. The flask was charged with 41.1 mlof a solution of sodium hydroxide in ethanol (0.49N, 20.1 mmol), 8.9 mlof ethanol, water (0 to 40 mol. eq., according to the crystal formdesired), and 5 g (20.1 mmol) of anhydrous alendronic acid. The reactionmixture was boiled with vigorous stirring for about 15 hours until theof pH of the liquid phase remained constant (approx. pH 7). Aftercooling of the reaction mixture to ambient temperature, the solidmaterial was filtered, washed with absolute ethanol, and dried overnightin a vacuum oven (10-15 mmHg, ambient temperature) to give 96-99% sodiumalendronate having the following crystal forms: crystal Form D, when 0-4(preferably 0-2) mol. eq. water were used; crystal Form F, when 5-8(preferably 6-7) mol. eq. water were used; crystal Form E, when 9-15(preferably 12) mol. eq. water were used; and crystal Form G, when 15-40(preferably 25-35) mol. eq. water were used. The monosodium salt wasconfirmed by atomic absorption and by measuring the pH of a 0.5% aqueoussolution of the salt (approx. pH 4.4).

Example 4 Preparation of Alendronate Sodium from Alendronic AcidMonohydrate

[0090] A 250 ml flask was fitted with a mechanical stirrer, athermometer, and a reflux condenser. The flask was charged with 38.2 mlof a solution of sodium hydroxide in ethanol (0.49 N, 18.7 mmol), 4.8 mlof ethanol, water (0 to 100 mol. eq., according to the crystal formdesired), and 5 g (18.7 mmol) of alendronic acid monohydrate. Thereaction mixture was boiled with vigorous stirring for about 15 hoursuntil stability of pH of the liquid phase was reached (approx. pH 7).After cooling of the reaction mixture to ambient temperature theprecipitate was filtered, washed with absolute ethanol, and driedovernight in a vacuum over (10-15 mm Hg, ambient temperature) to give96-99% sodium alendronate having the following crystalline forms:crystalline Form B, when 0-4 (preferably 0-2) mol. eq. water were used;crystalline Form F, when 3-5 mol. eq. water were used; crystalline FormE, when 11-13 (preferably 12) mol. eq. water were used; and crystallineForm G, when 15-100 (preferably 20-80) mol. eq. water were used.

[0091] The monosodium salt was confirmed by atomic absorption and bymeasuring the pH of a 0.5% aqueous solution of the salt (approx. pH4.4).

[0092] The water content is determined using the TGA technique, heatingthe sample to 230° C. and calculating the sharp LOD (loss on drying)step, which occurs above 150° C.

Example 5 Preparation of Sodium Alendronate Dihydrate

[0093] A one liter flask was fitted with a magnetic bar stirrer, Soxhletextraction funnel (operating volume 150 ml) charged with 3 Å molecularsieves (60 g), and reflux condenser connected to a drying tube with 3 Åmolecular sieves. The flask was charged with sodium alendronatetrihydrate (25 g) and absolute ethanol (450 ml, vol. % of water<0.1%).The mixture was boiled with stirring for 24 hours. After cooling toambient temperature the solid material was filtered, washed withabsolute ethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg,ambient temperature) to give sodium alendronate dehydrate.

Example 6 Preparation of Sodium Alendronate Monohydrate

[0094] A one liter flask was fitted with a magnetic bar stirrer, Soxhletextraction funnel (operating volume 150 ml) charged with 3 Å molecularsieves (60 g), and reflux condenser connected to a drying tube with 3 Åmolecular sieves. The flask was charged with sodium alendronatetrihydrate (25 g) and absolute ethanol (450 ml, vol. % of water<0.1%).The mixture was boiled with stirring for, 24 hours. After cooling toambient temperature, the used molecular sieves were replaced by a newportion of 3 Å molecular sieves (60 g) and the reflux was continued foradditional 24 hours. After cooling to ambient temperature the solidmaterial was filtered, washed with absolute ethyl ether, and driedovernight in a vacuum oven (10-15 mm Hg, ambient temperature) to givesodium alendronate monohydrate.

Example 7 Preparation of Alendronate Sodium Form G from Alendronic AcidMono hydrate

[0095] Preparation of Aqueous Ethanolic Sodium Hydroxide

[0096] Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) weremixed. Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in45 ml of this aqueous ethanol. The remaining aqueous ethanol was used toprepare a suspension of alendronic acid monohydrate.

[0097] A one liter flask was fitted with a mechanical stirrer, athermometer, and a reflux condenser. The flask was charged withalendronic acid monohydrate (25 g, 0.094 mol) and aqueous ethanol. Themixture was heated to boiling with stirring. The aqueous ethanolicsodium hydroxide was added dropwise to the suspension of alendronic acidmonohydrate in aqueous ethanol for 3 hours at reflux with vigorouslystirring. Then the mixture was stirred at reflux for additional 15hours. The mixture was cooled to room temperature with stirring. Thesolid was filtered, washed with absolute ethanol, then with absoluteethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, ambienttemperature) to give 26.2 g of alendronate sodium, having crystallineForm G.

Example 8 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

[0098] Preparation of Aqueous Ethanolic Sodium Hydroxide

[0099] Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) weremixed. Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in45 ml of this aqueous ethanol. The remaining aqueous ethanol was used toprepare a suspension of alendronic acid monohydrate.

[0100] A one liter flask was fitted with a mechanical stirrer, athermometer, and a reflux condenser. The flask was charged withalendronic acid monohydrate (25 g, 0.094 mol) and aqueous ethanol. Themixture was heated to boiling with stirring. The aqueous ethanolicsodium hydroxide was added dropwise to the suspension of alendronic acidmonohydrate in aqueous ethanol for 3 hours at reflux with vigorouslystirring. Then the mixture was stirred at reflux for additional 15hours. The mixture was cooled to room temperature with stirring. Thesolid was filtered, washed with absolute ethanol, and dried overnight ina vacuum oven (10-15 mm Hg, ambient temperature) to give 26.2 g ofalendronate sodium, having crystalline Form G.

Example 9 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

[0101] Preparation of Aqueous Ethanolic Sodium Hydroxide

[0102] Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) weremixed. Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in45 ml of this aqueous ethanol. The remaining aqueous ethanol was used toprepare a suspension of alendronic acid monohydrate.

[0103] A one liter flask was fitted with a mechanical stirrer, athermometer, and a reflux. condenser. The flask was charged withalendronic acid monohydrate (25 g, 0.094 mol) and aqueous ethanol. Themixture was heated to boiling with stirring. The aqueous ethanolicsodium hydroxide was added dropwise to the suspension of alendronic acidmonohydrate in aqueous ethanol for 3 hours at reflux with vigorouslystirring. Then the mixture was stirred at reflux for additional 15hours. The mixture was cooled to room temperature with stirring. Thesolid was filtered, washed with absolute ethanol, and dried overnight ina vacuum oven (10-15 mm Hg, 40-50° C.) to give 26.2g of alendronatesodium, having crystalline Form G.

Example 10 Preparation of Alendronate Sodium Form G from Alendronic AcidMonohydrate

[0104] Preparation of Aqueous Ethanolic Sodium Hydroxide

[0105] Absolute ethanol (250 ml) and water (59 ml, 35×0.094 mol) weremixed. Sodium hydroxide (3.8 g, assay 99%, 0.094 mol) was dissolved in45 ml of this aqueous ethanol. The remaining aqueous ethanol was used toprepare a suspension of alendronic acid monohydrate.

[0106] A one liter flask was fitted with a mechanical stirrer, athermometer, and a reflux condenser. The flask was charged withalendronic acid monohydrate (25 g, 0.094 mol) and aqueous ethanol. Themixture was heated to boiling with stirring. The aqueous ethanolicsodium hydroxide was added dropwise to the suspension of alendronic acidmonohydrate in aqueous ethanol for 3 hours at reflux with vigorouslystirring. Then the mixture was stirred at reflux for additional 15hours. The mixture was cooled to room temperature with stirring. Thesolid was filtered, washed with absolute ethanol, then with absoluteethyl ether, and dried overnight in a vacuum oven (10-15 mm Hg, 40-50°C.) to give 26.2 g of alendronate sodium, having crystalline Form G.

Example 11 Preparation of Alendronate Sodium Form (G) from AlendronateSodium Trihydrate

[0107] A suspension of alendronate sodium trihydrate 1.0 g (3.08 mmol)in aqueous ethanol (10 ml of ethanol+1.9 ml of water) was boiled atreflux with stirring for 15 hrs. After cooling to ambient temperaturethe solid was filtered, washed with absolute ethanol and ether, anddried overnight in a vacuum oven (10-15 mm Hg, ambient temperature) togive 0.9 g of alendronate sodium, containing crystal form G.

Example 12 Preparation of Alendronate Sodium Form H from Alendronic AcidMonohydrate

[0108] Preparation of Aqueous Ethanolic Sodium Hydroxide

[0109] Absolute ethanol (50 ml) and water (6.7 ml, 20×0.019 mol) weremixed. Sodium hydroxide (0.76 g, assay 99%, 0.019 mol) was dissolved in8.5 ml of this aqueous ethanol. The remaining aqueous ethanol was usedto prepare a suspension of alendronic acid monohydrate.

[0110] A 250 ml flask was fitted with a mechanical stirrer, athermometer, a dropping funnel, and a reflux condenser. The flask wascharged with alendronic acid monohydrate (5 g, 0.019 mol) and aqueousethanol. The aqueous ethanolic sodium hydroxide was added dropwise tothe suspension of alendronic acid monohydrate in aqueous ethanol for 15minutes at reflux with vigorously stirring. The mixture was thenrefluxed for additional 15 hours. The mixture was then cooled to roomtemperature with stirring. The solid was filtered, washed with absoluteethanol, then with absolute ethyl ether, and dried overnight in a vacuumoven (10-15 mm Hg, ambient temperature) to give 5.2 g of alendronatesodium, having crystalline Form H.

[0111] Although certain presently preferred embodiments of the inventionhave been described herein, it will be apparent to those skilled in theart to which the invention pertains that variations and modifications ofthe described embodiments may be made without departing from the spiritand scope of the invention. Accordingly, it is intended that theinvention be limited only to the extent required by the appended claimsand the applicable rules of law.

We claim:
 1. The compound 4-amino-1-hydroxybutylidene-1, 1-bisphosphonicacid monosodium salt having water content of 1.3% to 11.7%.
 2. A hydrateform of a compound of claim 1 which is any of the hydrate forms selectedfrom the group that consists of 1/4 hydrate, 1/3 hydrate, hemihydrate,2/3 hydrate, 3/4 hydrate, monohydrate, 5/4 hydrate, 4/3 hydrate, 3/2hydrate, and dehydrate.
 3. The compound4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salthaving water content of 5.1% to 7.0%.
 4. The compound according to claim3 having water content of about 6.2%.
 5. Alendronate monosodiummonohydrate.
 6. The compound according to claim 3, which ischaracterized by peaks in the powder xray diffraction at values of twotheta of 12.7±0.2, 16.2±0.2, 17.3±0.2, 17.6±0.2, 24.8±0.2, and 25.5±0.2.7. A method of preparing the compound of any of claims 3 through 6comprising the steps of: a) reacting one equivalent of4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid with one equivalentof sodium base in a lower alkanol comprising 5 to 200 equivalents ofwater; and b) isolating said compound of any of claims 3 through
 6. 8. Amethod according to claim 7 wherein the compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid is in a monohydrateform.
 9. A method according to claim 7 wherein the lower alkanol isselected from the group consisting of methanol, ethanol and isopropanol.10. A method according to claim 7 wherein the sodium base is selectedfrom the group consisting of sodium hydroxide, sodium methoxide andsodium ethoxide.
 11. A method according to claim 7 wherein the compound4-amino-1-hydroxybutylidene-1,1bisphosphonic acid is is in an anhydrousform.
 12. A method of preparing the compound of any of claims 3 through6 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic monosodium salt in a lower alkanol with 20-40equivalents of water; and b) isolating said compound of any of claims 3through
 6. 13. A method according to claim 12 wherein the lower alkanolof step a) is ethanol.
 14. A method of preparing the compound of any ofclaims 3 through 6 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic disodium salt in a loweralkanol with 20-40 equivalents of water, and one equivalent ofalendronic acid; and b) isolating said compound of any of claims 3through
 6. 15. A method according to claim 14 wherein the lower alkanolof step a) is ethanol.
 16. A method of preparing the compound of any ofclaims 3 through 6 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic trisodium salt in a loweralkanol with 20-40 equivalents of water and two equivalents ofalendronic acid; and b) isolating said compound of any of claims 3through
 6. 17. A method according to claim 16 wherein the lower alkanolof step a) is ethanol.
 18. A method of preparing the compound of any ofclaims 3 through 6 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic tetrasodium salt in alower alkanol with 20-40 equivalents of water and three equivalents ofalendror acid; and b) isolating said compound of any of claims 3 through6.
 19. A method according to claim 18 wherein the lower alkanol of stepa) is ethanol.
 20. A method according to claim 12 in which the4-amino-1-hydroxybutylidene-1, 1-bisphosphonic sodium salt is amonosodium salt trihydrate.
 21. A compound according to claim 3, whichis characterized by peaks in the powder x-ray diffraction at values oftwo theta of 9.3±0.2, 12.4±0.2, 13.5±0.2, 26.3±0.2 and 30.0±0.2.
 22. Amethod of preparing the compound of claim 21 comprising the steps of: a)treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic monosodiumtrihydrate with an effective amount of a drying agent; and b) isolatingsaid compound of claim
 21. 23. A method according to claim 22 whereinthe reaction of step a) is performed in ethanol.
 24. Alendronatemonosodium hemihydrate.
 25. The compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt having water content of 2.8% to3.9%.
 26. The compound according to claim 25 having water content ofabout 3.2%.
 27. The compound according to claim 25, which ischaracterized by peaks in the powder x-ray diffraction at values of twotheta of 7.0±0.2, 9.3±0.2, and 14.0±0.2.
 28. A method of preparing thecompound of claim 24 or 25 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid in a lower alkanolwith one equivalent of sodium base and 9 to 15 equivalents of water; andb) isolating said compound of claim 24 or
 25. 29. A method according toclaim 28 wherein the compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is in a monohydrate form.
 30. A method according toclaim 28 wherein the lower alkanol is selected from the group consistingof methanol, ethanol and isopropanol.
 31. A method according to claim 28wherein the sodium base is selected from the group consisting of sodiumhydroxide, sodium methoxide and sodium ethoxide.
 32. A method accordingto claim 28 wherein the compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is in an anhydrous form.
 33. The compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salthaving water content of 2.5% to 3.5%.
 34. The compound according toclaim 33, which is characterized by peaks in the powder x-raydiffraction at values of two theta of 9.2±0.2, 14.2±0.2, 15.0±0.2,17.1±0.2, 20.7±0.2, 22.0±0.2, 22.4±0.2.
 35. A method of preparing thecompound of claim 2 or 33 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid in a lower alkanolwith one equivalent of sodium base and 17 to 22 equivalents of water;and b) isolating said compound of claim 2 or
 33. 36. A method accordingto claim 35 in which the compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is in a monohydrate form.
 37. A method according toclaim 35 wherein the lower alkanol is selected from the group consistingof methanol, ethanol and isopropanol.
 38. A method according to claim 35wherein the sodium base is selected from the group consisting of sodiumhydroxide, sodium methoxide and sodium ethoxide.
 39. The compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salthaving water content of 6.4% to 9.0%.
 40. The compound according toclaim 39, which is characterized by peaks in the powder x-raydiffraction at values of two theta of 12.2±0.2, 13.3±0.2, 14.8±0.2,15.8±0.2, 16.3±0.2, and 17.2±0.2.
 41. A method of preparing the compoundof claim 2 or 39 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid in a lower alkanolwith one equivalent of sodium base and 0 to 4 equivalents of water; andb) isolating said compound of claim 2 or
 39. 42. A method according toclaim 41 in which the compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid is in a monohydrate form.
 43. A method according toclaim 41 wherein the lower alkanol is selected from the group consistingof methanol, ethanol and isopropanol.
 44. A method according to claim 41wherein the sodium base is selected from the group consisting of sodiumhydroxide, sodium methoxide and sodium ethoxide.
 45. The compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salthaving water content of 3.2% to 5.8%.
 46. The compound according toclaim 45, which is characterized by peaks in the powder x-raydiffraction at values of two theta of 13.1±0.2, 15.2±0.2, 16.3±0.2,22.3±0.2, 22.5±0.2, 23.4±0.2, and 23.7±0.2.
 47. A method of preparingthe compound of 2 or 45 comprising the steps of: a) treating4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid anhydrous in a loweralkanol with one equivalent of sodium base and 0 to 4 equivalents ofwater; and b) isolating said compound of claim 2 or
 45. 48. A methodaccording to claim 47 in which the compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid is in an anhydrousform.
 49. A method according to claim 48 wherein the lower alkanol isselected from the group consisting of methanol, ethanol and isopropanol.50. A method according to claim 48 wherein the sodium base is selectedfrom the group consisting of sodium hydroxide, sodium methoxide andsodium ethoxide.
 51. The compound 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt having water content of 1.3,% to3.1%.
 52. The compound according to claim 51, which is characterized bypeaks in the powder x-ray diffraction at values of two theta of13.0±0.2, 13.4±0.2, 14.2±0.2, 19.1±0.2, and 19.4±0.2.
 53. A method ofpreparing the compound of claim 2 or 51 comprising the steps of: a)treating 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid in a loweralkanol with one equivalent of sodium base and 3 to 20 equivalents ofwater; and b) isolating said compound of claim 2 or
 51. 54. A methodaccording to claim 53 in which the compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid is in a monohydrateform.
 55. A method according to claim 53 wherein the lower alkanol isselected from the group consisting of methanol, ethanol and isopropanol.56. A method according to claim 53 wherein the sodium base is selectedfrom the group consisting of sodium hydroxide, sodium methoxide andsodium ethoxide.
 57. A method according to claim 53 wherein the compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid is in an anhydrousform.
 58. Alendronate monosodium dihydrate.
 59. The compound4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salthaving water content of about 11.7%.
 60. The compound according to claim59, which is characterized by peaks in the powder x-ray diffraction atvalues of two theta of 9.3±0.2, 12.4±0.2, 13.5±0.2, 26.3±0.2 and30.0±0.2.
 61. A method for preparing a compound according to claim 58 or59 comprising the steps of: a) treating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate with an effective amountof drying agent; and b) isolating 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid the monosodium salt dihydrate.
 62. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof any of claims 1, 3, 25, 33, 39, 45 and
 51. 63. A method for treatingand/or preventing bone loss in a subject, comprising the step ofadministering to said subject in need thereof an effective amount of thepharmaceutical composition as defined in claim
 62. 64. A method ofpreparing the compound of claim 1 comprising the steps of: a) reactingone equivalent of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acidwith one equivalent of sodium base in an aqueous organic solventselected from the group consisting of acetone, DMSO, DMF, acetonitrile,alcohols, polyalcohols, polyalcohol ethers, pyridine, sulfolane,N-methyl pyrrolidinone and dioxane, and b) isolating said compound ofclaim
 1. 65. A method of preparing the compound of claim 3 comprisingthe steps of: a) reacting one equivalent of4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid with one equivalentof sodium base in an aqueous organic solvent selected from the groupconsisting of acetone, DMSO, DMF, acetonitrile, alcohols, polyalcohols,polyalcohol ethers, pyridine, sulfolane, N-methyl pyrrolidinone anddioxane, and b) isolating said compound of claim
 3. 66. A method ofpreparing the compound of claim 25 comprising the steps of: a) reactingone equivalent of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acidwith one equivalent of sodium base in an aqueous organic solventselected from the group consisting of acetone, DMSO, DMF, acetonitrile,alcohols, polyalcohols, polyalcohol ethers, pyridine, sulfolane,N-methyl pyrrolidinone and dioxane, and b) isolating said compound ofclaim
 25. 67. A method of preparing the compound of claim 33 comprisingthe steps of: a) reacting one equivalent of4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid with one equivalentof sodium base in an aqueous organic solvent selected from the groupconsisting of acetone, DMSO, DMF, acetonitrile, alcohols, polyalcohols,polyalcohol ethers, pyridine, sulfolane, N-methyl pyrrolidinone anddioxane, and b) isolating said compound of claim
 33. 68. A method ofpreparing the compound of claim 39 comprising the steps of: a) reactingone equivalent of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acidwith one equivalent of sodium base in an aqueous organic solventselected from the group consisting of acetone, DMSO, DMF, acetonitrile,alcohols, polyalcohols, polyalcohol ethers, pyridine, sulfolane,N-methyl pyrrolidinone and dioxane, and b) isolating said compound ofclaim
 39. 69. A method of preparing the compound of claim 45 comprisingthe steps of: a) reacting one equivalent of4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid with one equivalentof sodium base in an aqueous organic solvent selected from the groupconsisting of acetone, DMSO, DMF, acetonitrile, alcohols, polyalcohols,polyalcohol ethers, pyridine, sulfolane, N-methyl pyrrolidinone anddioxane, and b) isolating said compound of claim
 45. 70. A method ofpreparing the compound of claim 51 comprising the steps of: a) reactingone equivalent of 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acidwith one equivalent of sodium base in an aqueous organic solventselected from the group consisting of acetone, DMSO, DMF, acetonitrile,alcohols, polyalcohols, polyalcohol ethers, pyridine, sulfolane,N-methyl pyrrolidinone and dioxane, and b) isolating said compound ofclaim
 51. 71. A method of preparing the compound of claim 59 comprisingthe steps of: a) reacting one equivalent of4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid with one equivalentof sodium base in an aqueous organic solvent selected from the groupconsisting of acetone, DMSO, DMF, acetonitrile, alcohols, polyalcohols,polyalcohol ethers, pyridine, sulfolane, N-methyl pyrrolidinone anddioxane, and b) isolating said compound of claim 59.